The TRAP complex was first purified in the Roeder laboratory and shown to be involved in multiple transcriptional regulatory pathways. The most important subunit of this complex for nuclear receptor function is TRAP220, since it binds to nuclear receptors in a ligand-dependent manner and thus anchors the entire complex to promoter-bound receptors. TRAP220 is found to bind and to enhance transcription activation by several nuclear receptors in a ligand-dependent manner both in cell free systems and in some cell culture models with transfected genes. However, there are no true in vivo studies that directly link TRAP220 to nuclear receptor function. The major goal of this proposal is to better understand the function of TRAP220 in vivo. Two systems will be used in this study. The first will investigate the roles of TRAP220 in (i) cell culture models that use TRAP220-/-MEF cells expressing low level of nuclear receptors and/or bearing integrated reporters and (ii) in established cell lines with well-characterized hormone responses using RNAi knock down methods. The second will investigate the in vivo roles of TRAP220 in mouse models using approaches (chimeric mice and tissue-specific TRAP220 knock out mice) that bypass the embryonic lethal stage.